Project acronym ALZSYN
Project Imaging synaptic contributors to dementia
Researcher (PI) Tara Spires-Jones
Host Institution (HI) THE UNIVERSITY OF EDINBURGH
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary Alzheimer's disease, the most common cause of dementia in older people, is a devastating condition that is becoming a public health crisis as our population ages. Despite great progress recently in Alzheimer’s disease research, we have no disease modifying drugs and a decade with a 99.6% failure rate of clinical trials attempting to treat the disease. This project aims to develop relevant therapeutic targets to restore brain function in Alzheimer’s disease by integrating human and model studies of synapses. It is widely accepted in the field that alterations in amyloid beta initiate the disease process. However the cascade leading from changes in amyloid to widespread tau pathology and neurodegeneration remain unclear. Synapse loss is the strongest pathological correlate of dementia in Alzheimer’s, and mounting evidence suggests that synapse degeneration plays a key role in causing cognitive decline. Here I propose to test the hypothesis that the amyloid cascade begins at the synapse leading to tau pathology, synapse dysfunction and loss, and ultimately neural circuit collapse causing cognitive impairment. The team will use cutting-edge multiphoton and array tomography imaging techniques to test mechanisms downstream of amyloid beta at synapses, and determine whether intervening in the cascade allows recovery of synapse structure and function. Importantly, I will combine studies in robust models of familial Alzheimer’s disease with studies in postmortem human brain to confirm relevance of our mechanistic studies to human disease. Finally, human stem cell derived neurons will be used to test mechanisms and potential therapeutics in neurons expressing the human proteome. Together, these experiments are ground-breaking since they have the potential to further our understanding of how synapses are lost in Alzheimer’s disease and to identify targets for effective therapeutic intervention, which is a critical unmet need in today’s health care system.
Summary
Alzheimer's disease, the most common cause of dementia in older people, is a devastating condition that is becoming a public health crisis as our population ages. Despite great progress recently in Alzheimer’s disease research, we have no disease modifying drugs and a decade with a 99.6% failure rate of clinical trials attempting to treat the disease. This project aims to develop relevant therapeutic targets to restore brain function in Alzheimer’s disease by integrating human and model studies of synapses. It is widely accepted in the field that alterations in amyloid beta initiate the disease process. However the cascade leading from changes in amyloid to widespread tau pathology and neurodegeneration remain unclear. Synapse loss is the strongest pathological correlate of dementia in Alzheimer’s, and mounting evidence suggests that synapse degeneration plays a key role in causing cognitive decline. Here I propose to test the hypothesis that the amyloid cascade begins at the synapse leading to tau pathology, synapse dysfunction and loss, and ultimately neural circuit collapse causing cognitive impairment. The team will use cutting-edge multiphoton and array tomography imaging techniques to test mechanisms downstream of amyloid beta at synapses, and determine whether intervening in the cascade allows recovery of synapse structure and function. Importantly, I will combine studies in robust models of familial Alzheimer’s disease with studies in postmortem human brain to confirm relevance of our mechanistic studies to human disease. Finally, human stem cell derived neurons will be used to test mechanisms and potential therapeutics in neurons expressing the human proteome. Together, these experiments are ground-breaking since they have the potential to further our understanding of how synapses are lost in Alzheimer’s disease and to identify targets for effective therapeutic intervention, which is a critical unmet need in today’s health care system.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-11-01, End date: 2021-10-31
Project acronym ART
Project Aberrant RNA degradation in T-cell leukemia
Researcher (PI) Jan Cools
Host Institution (HI) VIB
Call Details Consolidator Grant (CoG), LS4, ERC-2013-CoG
Summary "The deregulation of transcription is an important driver of leukemia development. Typically, transcription in leukemia cells is altered by the ectopic expression of transcription factors, by modulation of signaling pathways or by epigenetic changes. In addition to these factors that affect the production of RNAs, also changes in the processing of RNA (its splicing, transport and decay) may contribute to determine steady-state RNA levels in leukemia cells. Indeed, acquired mutations in various genes encoding RNA splice factors have recently been identified in myeloid leukemias and in chronic lymphocytic leukemia. In our study of T-cell acute lymphoblastic leukemia (T-ALL), we have identified mutations in RNA decay factors, including mutations in CNOT3, a protein believed to function in deadenylation of mRNA. It remains, however, unclear how mutations in RNA processing can contribute to the development of leukemia.
In this project, we aim to further characterize the mechanisms of RNA regulation in T-cell acute lymphoblastic leukemia (T-ALL) to obtain insight in the interplay between RNA generation and RNA decay and its role in leukemia development. We will study RNA decay in human T-ALL cells and mouse models of T-ALL, with the aim to identify the molecular consequences that contribute to leukemia development. We will use new technologies such as RNA-sequencing in combination with bromouridine labeling of RNA to measure RNA transcription and decay rates in a transcriptome wide manner allowing unbiased discoveries. These studies will be complemented with screens in Drosophila melanogaster using an established eye cancer model, previously also successfully used for the studies of T-ALL oncogenes.
This study will contribute to our understanding of the pathogenesis of T-ALL and may identify new targets for therapy of this leukemia. In addition, our study will provide a better understanding of how RNA processing is implicated in cancer development in general."
Summary
"The deregulation of transcription is an important driver of leukemia development. Typically, transcription in leukemia cells is altered by the ectopic expression of transcription factors, by modulation of signaling pathways or by epigenetic changes. In addition to these factors that affect the production of RNAs, also changes in the processing of RNA (its splicing, transport and decay) may contribute to determine steady-state RNA levels in leukemia cells. Indeed, acquired mutations in various genes encoding RNA splice factors have recently been identified in myeloid leukemias and in chronic lymphocytic leukemia. In our study of T-cell acute lymphoblastic leukemia (T-ALL), we have identified mutations in RNA decay factors, including mutations in CNOT3, a protein believed to function in deadenylation of mRNA. It remains, however, unclear how mutations in RNA processing can contribute to the development of leukemia.
In this project, we aim to further characterize the mechanisms of RNA regulation in T-cell acute lymphoblastic leukemia (T-ALL) to obtain insight in the interplay between RNA generation and RNA decay and its role in leukemia development. We will study RNA decay in human T-ALL cells and mouse models of T-ALL, with the aim to identify the molecular consequences that contribute to leukemia development. We will use new technologies such as RNA-sequencing in combination with bromouridine labeling of RNA to measure RNA transcription and decay rates in a transcriptome wide manner allowing unbiased discoveries. These studies will be complemented with screens in Drosophila melanogaster using an established eye cancer model, previously also successfully used for the studies of T-ALL oncogenes.
This study will contribute to our understanding of the pathogenesis of T-ALL and may identify new targets for therapy of this leukemia. In addition, our study will provide a better understanding of how RNA processing is implicated in cancer development in general."
Max ERC Funding
1 998 300 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym BAS-SBBT
Project Bacterial Amyloid Secretion: Structural Biology and Biotechnology.
Researcher (PI) Han Karel Remaut
Host Institution (HI) VIB
Call Details Consolidator Grant (CoG), LS1, ERC-2014-CoG
Summary Curli are functional amyloid fibers that constitute the major protein component of the extracellular matrix in pellicle biofilms formed by Bacteroidetes and Proteobacteria. Unlike the protein misfolding and aggregation events seen in pathological amyloid diseases such as Alzheimer’s and Parkinson’s disease, curli are the product of a dedicated protein secretion machinery. Curli formation requires a specialised and mechanistically unique transporter in the bacterial outer membrane, as well as two soluble accessory proteins thought to facilitate the safe guidance of the curli subunits across the periplasm and to coordinate their self-assembly at cell surface.
In this interdisciplinary research program we will study the structural and molecular biology of E. coli curli biosynthesis and address the fundamental questions concerning the molecular processes that allow the spatially and temporally controlled transport and deposition of these pro-amyloidogenic polypeptides. We will structurally unravel the secretion machinery, trap and analyse critical secretion intermediates and through in vitro reconstitution, assemble a minimal, self-sufficient peptide transport and fiber assembly system.
The new insights gained will set the stage for targeted interventions in curli -mediated biofilm formation and this research project will develop a new framework to harness the unique properties found in curli structure and biosynthesis for biotechnological applications as in patterned functionalized nanowires and directed, selective peptide carriers.
Summary
Curli are functional amyloid fibers that constitute the major protein component of the extracellular matrix in pellicle biofilms formed by Bacteroidetes and Proteobacteria. Unlike the protein misfolding and aggregation events seen in pathological amyloid diseases such as Alzheimer’s and Parkinson’s disease, curli are the product of a dedicated protein secretion machinery. Curli formation requires a specialised and mechanistically unique transporter in the bacterial outer membrane, as well as two soluble accessory proteins thought to facilitate the safe guidance of the curli subunits across the periplasm and to coordinate their self-assembly at cell surface.
In this interdisciplinary research program we will study the structural and molecular biology of E. coli curli biosynthesis and address the fundamental questions concerning the molecular processes that allow the spatially and temporally controlled transport and deposition of these pro-amyloidogenic polypeptides. We will structurally unravel the secretion machinery, trap and analyse critical secretion intermediates and through in vitro reconstitution, assemble a minimal, self-sufficient peptide transport and fiber assembly system.
The new insights gained will set the stage for targeted interventions in curli -mediated biofilm formation and this research project will develop a new framework to harness the unique properties found in curli structure and biosynthesis for biotechnological applications as in patterned functionalized nanowires and directed, selective peptide carriers.
Max ERC Funding
1 989 489 €
Duration
Start date: 2015-06-01, End date: 2020-05-31
Project acronym BCELLMECHANICS
Project Regulation of antibody responses by B cell mechanical activity
Researcher (PI) Pavel Tolar
Host Institution (HI) IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Call Details Consolidator Grant (CoG), LS6, ERC-2014-CoG
Summary The production of antibodies against pathogens is an effective mechanism of protection against a wide range of infections. However, some pathogens evade antibody responses by rapidly changing their composition. Designing vaccines that elicit antibody responses against invariant parts of the pathogen is a rational strategy to combat existing and emerging pathogens. Production of antibodies is initiated by binding of B cell receptors (BCRs) to foreign antigens presented on the surfaces of antigen presenting cells. This binding induces B cell signalling and internalisation of the antigens for presentation to helper T cells. Although it is known that T cell help controls B cell expansion and differentiation into antibody-secreting and memory B cells, how the strength of antigen binding to the BCR regulates antigen internalisation remains poorly understood. As a result, the response and the affinity maturation of individual B cell clones are difficult to predict, posing a problem for the design of next-generation vaccines. My aim is to develop an understanding of the cellular mechanisms that underlie critical B cell activation steps. My laboratory has recently described that B cells use mechanical forces to extract antigens from antigen presenting cells. We hypothesise that application of mechanical forces tests BCR binding strength and thereby regulates B cell clonal selection during antibody affinity maturation and responses to pathogen evasion. We propose to test this hypothesis by (1) determining the magnitude and timing of the forces generated by B cells, and (2) determining the role of the mechanical properties of BCR-antigen bonds in affinity maturation and (3) in the development of broadly neutralising antibodies. We expect that the results of these studies will contribute to our understanding of the mechanisms that regulate the antibody repertoire in response to infections and have practical implications for the development of vaccines.
Summary
The production of antibodies against pathogens is an effective mechanism of protection against a wide range of infections. However, some pathogens evade antibody responses by rapidly changing their composition. Designing vaccines that elicit antibody responses against invariant parts of the pathogen is a rational strategy to combat existing and emerging pathogens. Production of antibodies is initiated by binding of B cell receptors (BCRs) to foreign antigens presented on the surfaces of antigen presenting cells. This binding induces B cell signalling and internalisation of the antigens for presentation to helper T cells. Although it is known that T cell help controls B cell expansion and differentiation into antibody-secreting and memory B cells, how the strength of antigen binding to the BCR regulates antigen internalisation remains poorly understood. As a result, the response and the affinity maturation of individual B cell clones are difficult to predict, posing a problem for the design of next-generation vaccines. My aim is to develop an understanding of the cellular mechanisms that underlie critical B cell activation steps. My laboratory has recently described that B cells use mechanical forces to extract antigens from antigen presenting cells. We hypothesise that application of mechanical forces tests BCR binding strength and thereby regulates B cell clonal selection during antibody affinity maturation and responses to pathogen evasion. We propose to test this hypothesis by (1) determining the magnitude and timing of the forces generated by B cells, and (2) determining the role of the mechanical properties of BCR-antigen bonds in affinity maturation and (3) in the development of broadly neutralising antibodies. We expect that the results of these studies will contribute to our understanding of the mechanisms that regulate the antibody repertoire in response to infections and have practical implications for the development of vaccines.
Max ERC Funding
1 999 386 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym BEAL
Project Bioenergetics in microalgae : regulation modes of mitochondrial respiration, photosynthesis, and fermentative pathways, and their interactions in secondary algae
Researcher (PI) Pierre Antoine Georges Cardol
Host Institution (HI) UNIVERSITE DE LIEGE
Call Details Consolidator Grant (CoG), LS8, ERC-2015-CoG
Summary During the course of eukaryote evolution, photosynthesis was propagated from primary eukaryotic algae to non-photosynthetic organisms through multiple secondary endosymbiotic events. Collectively referred to as “secondary algae”, these photosynthetic organisms account for only 1-2% of the total global biomass, but produce a far larger part of the global annual fixation of carbon on Earth.
ATP is the universal chemical energy carrier in living cells. In photosynthetic eukaryotes, it is produced by two major cellular processes: photosynthesis and respiration taking place in chloroplasts and mitochondria, respectively. Both processes support the production of biomass and govern gas (O2 and CO2) exchanges. On the other hand, anaerobic fermentative enzymes have also been identified in several primary and secondary algae. The regulation modes and interactions of respiration, photosynthesis and fermentation are fairly well understood in primary green algae. Conversely, the complex evolutionary history of secondary algae implies a great variety of original regulatory mechanisms that have been barely investigated to date.
Over the last years my laboratory has developed and optimized a range of multidisciplinary approaches that now allow us, within the frame of the BEAL (BioEnergetics in microALgae) project, to (i) characterize and compare the photosynthetic regulation modes by biophysical approaches, (ii) use genetic and biochemical approaches to gain fundamental knowledge on aerobic respiration and anaerobic fermentative pathways, and (iii) investigate and compare interconnections between respiration, photosynthesis, and fermentation in organisms resulting from distinct evolutionary scenarios. On a long term, these developments will be instrumental to unravel bioenergetics constraints on growth in microalgae, a required knowledge to exploit the microalgal diversity in a biotechnological perspective, and to understand the complexity of the marine phytoplankton.
Summary
During the course of eukaryote evolution, photosynthesis was propagated from primary eukaryotic algae to non-photosynthetic organisms through multiple secondary endosymbiotic events. Collectively referred to as “secondary algae”, these photosynthetic organisms account for only 1-2% of the total global biomass, but produce a far larger part of the global annual fixation of carbon on Earth.
ATP is the universal chemical energy carrier in living cells. In photosynthetic eukaryotes, it is produced by two major cellular processes: photosynthesis and respiration taking place in chloroplasts and mitochondria, respectively. Both processes support the production of biomass and govern gas (O2 and CO2) exchanges. On the other hand, anaerobic fermentative enzymes have also been identified in several primary and secondary algae. The regulation modes and interactions of respiration, photosynthesis and fermentation are fairly well understood in primary green algae. Conversely, the complex evolutionary history of secondary algae implies a great variety of original regulatory mechanisms that have been barely investigated to date.
Over the last years my laboratory has developed and optimized a range of multidisciplinary approaches that now allow us, within the frame of the BEAL (BioEnergetics in microALgae) project, to (i) characterize and compare the photosynthetic regulation modes by biophysical approaches, (ii) use genetic and biochemical approaches to gain fundamental knowledge on aerobic respiration and anaerobic fermentative pathways, and (iii) investigate and compare interconnections between respiration, photosynthesis, and fermentation in organisms resulting from distinct evolutionary scenarios. On a long term, these developments will be instrumental to unravel bioenergetics constraints on growth in microalgae, a required knowledge to exploit the microalgal diversity in a biotechnological perspective, and to understand the complexity of the marine phytoplankton.
Max ERC Funding
1 837 625 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym BG-BB-AS
Project Birational Geometry, B-branes and Artin Stacks
Researcher (PI) Edward Paul Segal
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Consolidator Grant (CoG), PE1, ERC-2016-COG
Summary Derived categories of coherent sheaves on a variety are a fundamental tool in algebraic geometry. They also arise in String Theory, as the category of B-branes in a quantum field theory whose target space is the variety. This connection to physics has been extraordinarily fruitful, providing deep insights and conjectures.
An Artin stack is a sophisticated generalization of a variety, they encode the idea of equivariant geometry. A simple example is a vector space carrying a linear action of a Lie group. In String Theory this data defines a Gauged Linear Sigma Model, which is a basic tool in the subject. A GLSM should also give rise to a category of B-branes, but surprisingly it is not yet understood what this should be. An overarching goal of this project is to develop an understanding of this category (more accurately, system of categories), and to extend this understanding to more general Artin stacks.
The basic importance of this question is that in certain limits a GLSM reduces to a sigma model, whose target is a quotient of the vector space by the group. This quotient must be taken using Geometric Invariant Theory. Thus this project is intimately connected with the question of how derived categories change under variation-of-GIT, and birational maps in general.
For GLSMs with abelian groups this approach has already produced spectacular results, in the non-abelian case we understand only a few remarkable examples. We will develop these examples into a wide-ranging general theory.
Our key objectives are to:
- Provide powerful new tools for controlling the behaviour of derived categories under birational maps.
- Understand the category of B-branes on a large class of Artin stacks.
- Prove and apply a striking new duality between GLSMs.
- Construct completely new symmetries of derived categories.
Summary
Derived categories of coherent sheaves on a variety are a fundamental tool in algebraic geometry. They also arise in String Theory, as the category of B-branes in a quantum field theory whose target space is the variety. This connection to physics has been extraordinarily fruitful, providing deep insights and conjectures.
An Artin stack is a sophisticated generalization of a variety, they encode the idea of equivariant geometry. A simple example is a vector space carrying a linear action of a Lie group. In String Theory this data defines a Gauged Linear Sigma Model, which is a basic tool in the subject. A GLSM should also give rise to a category of B-branes, but surprisingly it is not yet understood what this should be. An overarching goal of this project is to develop an understanding of this category (more accurately, system of categories), and to extend this understanding to more general Artin stacks.
The basic importance of this question is that in certain limits a GLSM reduces to a sigma model, whose target is a quotient of the vector space by the group. This quotient must be taken using Geometric Invariant Theory. Thus this project is intimately connected with the question of how derived categories change under variation-of-GIT, and birational maps in general.
For GLSMs with abelian groups this approach has already produced spectacular results, in the non-abelian case we understand only a few remarkable examples. We will develop these examples into a wide-ranging general theory.
Our key objectives are to:
- Provide powerful new tools for controlling the behaviour of derived categories under birational maps.
- Understand the category of B-branes on a large class of Artin stacks.
- Prove and apply a striking new duality between GLSMs.
- Construct completely new symmetries of derived categories.
Max ERC Funding
1 358 925 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym BHSandAADS
Project The Black Hole Stability Problem and the Analysis of asymptotically anti-de Sitter spacetimes
Researcher (PI) Gustav HOLZEGEL
Host Institution (HI) IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Call Details Consolidator Grant (CoG), PE1, ERC-2017-COG
Summary The present proposal is concerned with the analysis of the Einstein equations of general relativity, a non-linear system of geometric partial differential equations describing phenomena from the bending of light to the dynamics of black holes. The theory has recently been confirmed in a spectacular fashion with the detection of gravitational waves.
The main objective of the proposal is to consolidate my research group based at Imperial College by developing novel mathematical techniques that will fundamentally advance our understanding of the Einstein equations. Here the proposal builds on mathematical progress in the last decade resulting from achievements in the fields of partial differential equations, differential geometry, microlocal analysis and theoretical physics.
The Black Hole Stability Problem
A major open problem in general relativity is to prove the non-linear stability of the Kerr family of black hole solutions. Recent advances in the problem of linear stability made by the PI and collaborators open the door to finally address a complete resolution of the stability problem. In this proposal we will describe what non-linear techniques will need to be developed in addition to achieve this goal. A successful resolution of this program would conclude an almost 50-year-old problem.
The Analysis of asymptotically anti-de Sitter (aAdS) spacetimes
We propose to prove the stability of pure AdS if so-called dissipative boundary conditions are imposed at the boundary. This result would align with the well-known stability results for the other maximally-symmetric solutions of the Einstein equations, Minkowski space and de Sitter space.
As a second -- related -- theme we propose to formulate and prove a unique continuation principle for the full non-linear Einstein equations on aAdS spacetimes. This goal will be achieved by advancing techniques that have recently been developed by the PI and collaborators for non-linear wave equations on aAdS spacetimes.
Summary
The present proposal is concerned with the analysis of the Einstein equations of general relativity, a non-linear system of geometric partial differential equations describing phenomena from the bending of light to the dynamics of black holes. The theory has recently been confirmed in a spectacular fashion with the detection of gravitational waves.
The main objective of the proposal is to consolidate my research group based at Imperial College by developing novel mathematical techniques that will fundamentally advance our understanding of the Einstein equations. Here the proposal builds on mathematical progress in the last decade resulting from achievements in the fields of partial differential equations, differential geometry, microlocal analysis and theoretical physics.
The Black Hole Stability Problem
A major open problem in general relativity is to prove the non-linear stability of the Kerr family of black hole solutions. Recent advances in the problem of linear stability made by the PI and collaborators open the door to finally address a complete resolution of the stability problem. In this proposal we will describe what non-linear techniques will need to be developed in addition to achieve this goal. A successful resolution of this program would conclude an almost 50-year-old problem.
The Analysis of asymptotically anti-de Sitter (aAdS) spacetimes
We propose to prove the stability of pure AdS if so-called dissipative boundary conditions are imposed at the boundary. This result would align with the well-known stability results for the other maximally-symmetric solutions of the Einstein equations, Minkowski space and de Sitter space.
As a second -- related -- theme we propose to formulate and prove a unique continuation principle for the full non-linear Einstein equations on aAdS spacetimes. This goal will be achieved by advancing techniques that have recently been developed by the PI and collaborators for non-linear wave equations on aAdS spacetimes.
Max ERC Funding
1 999 755 €
Duration
Start date: 2018-11-01, End date: 2023-10-31
Project acronym BIONICbacteria
Project Integrating a novel layer of synthetic biology tools in Pseudomonas, inspired by bacterial viruses
Researcher (PI) Rob LAVIGNE
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Call Details Consolidator Grant (CoG), LS9, ERC-2018-COG
Summary As nature’s first bioengineers, bacteriophages have evolved to modify, adapt and control their bacterial hosts through billions of years of interactions. Indeed, like modern synthetic biologists aspire to do, bacteriophages already evade bacterial silencing of their xenogeneic DNA, subvert host gene expression, and co-opt both the central and peripheral metabolisms of their hosts. Studying these key insights from a molecular systems biology perspective, inspired us to develop these evolutionary fully-adapted phage mechanisms as a next-level layer of synthetic biology tools. Thus, BIONICbacteria will provide conceptual novel synthetic biology tools that allow direct manipulation of specific protein activity, post-translational modifications, RNA stability, and metabolite concentrations.
The goal of BIONICbacteria is to pioneer an unconventional way to perform synthetic biology, tapping an unlimited source of novel phage tools genetic circuits and phage modulators. To achieve these goals, we will apply and develop state-of-the-art technologies in molecular microbiology and focus on three principal aims:
(1) To exploit new phage-encoded genetic circuits as synthetic biology parts and as intricate biotechnological chassis.
(2) To build synthetic phage modulators (SPMs) as novel payloads to directly impact the bacterial metabolism in a targeted manner.
(3) To create designer bacteria by integrating SPMs-containing circuits into bacterial strains as proof-of-concepts for applications in industrial fermentations and vaccine design.
This proposed “plug-in” approach of evolutionary-adapted synthetic modules, will allow us to domesticate Pseudomonas strains in radically new ways. By building proofs-of-concept for applications in industrial fermentations and vaccine development, we address key problem in these areas with potentially high-gain solutions for society and industry.
Summary
As nature’s first bioengineers, bacteriophages have evolved to modify, adapt and control their bacterial hosts through billions of years of interactions. Indeed, like modern synthetic biologists aspire to do, bacteriophages already evade bacterial silencing of their xenogeneic DNA, subvert host gene expression, and co-opt both the central and peripheral metabolisms of their hosts. Studying these key insights from a molecular systems biology perspective, inspired us to develop these evolutionary fully-adapted phage mechanisms as a next-level layer of synthetic biology tools. Thus, BIONICbacteria will provide conceptual novel synthetic biology tools that allow direct manipulation of specific protein activity, post-translational modifications, RNA stability, and metabolite concentrations.
The goal of BIONICbacteria is to pioneer an unconventional way to perform synthetic biology, tapping an unlimited source of novel phage tools genetic circuits and phage modulators. To achieve these goals, we will apply and develop state-of-the-art technologies in molecular microbiology and focus on three principal aims:
(1) To exploit new phage-encoded genetic circuits as synthetic biology parts and as intricate biotechnological chassis.
(2) To build synthetic phage modulators (SPMs) as novel payloads to directly impact the bacterial metabolism in a targeted manner.
(3) To create designer bacteria by integrating SPMs-containing circuits into bacterial strains as proof-of-concepts for applications in industrial fermentations and vaccine design.
This proposed “plug-in” approach of evolutionary-adapted synthetic modules, will allow us to domesticate Pseudomonas strains in radically new ways. By building proofs-of-concept for applications in industrial fermentations and vaccine development, we address key problem in these areas with potentially high-gain solutions for society and industry.
Max ERC Funding
1 998 750 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym BoneMalar
Project Mechanisms of bone marrow sequestration during malaria infection
Researcher (PI) Matthias Marti
Host Institution (HI) UNIVERSITY OF GLASGOW
Call Details Consolidator Grant (CoG), LS6, ERC-2015-CoG
Summary Malaria remains a major problem of public health in developing countries. It is responsible for about 600000 deaths per year, predominantly children in sub-Saharan Africa. There is an urgent need for novel therapies as resistance against current treatments is widespread. The complex parasite biology requires a multifaceted approach targeting multiple life cycle stages and virulence pathways. The pathogenesis of the most deadly of human malaria parasites, Plasmodium falciparum, is related to the capability of infected red blood cells to sequester in deep tissues. Sequestration is critical for the completion of the red blood cell cycle because the release of parasites into the blood circulation allows recognition by surveillance macrophages and clearance in the spleen. A series of studies have since led to the understanding that sequestration of asexually replicating parasites is caused by the adherence of parasite infected red blood cells to the vascular endothelium of various tissues in the body.
We have recently demonstrated that gametocytes, the only stage capable of transmission to the mosquito vector, develop in the extravascular environment of the human bone marrow. Preliminary studies in the mouse model have confirmed this finding and also suggest existence of an asexual reservoir in the bone marrow. In this innovative multidiscipinary proposal we aim to investigate the host pathogen interactions at the interface between infected red blood cell and bone marrow vasculature. Specifically we will focus on the following questions: how do parasites home to bone marrow? What are the changes in the bone marrow endothelium upon infection? How do parasites adhere with and transmigrate across the vascular endothelium in the bone marrow? The proposed studies initiate detailed characterization of a new paradigm in malaria parasite interaction with the host vasculature and provide a compelling new avenue for intervention strategies.
Summary
Malaria remains a major problem of public health in developing countries. It is responsible for about 600000 deaths per year, predominantly children in sub-Saharan Africa. There is an urgent need for novel therapies as resistance against current treatments is widespread. The complex parasite biology requires a multifaceted approach targeting multiple life cycle stages and virulence pathways. The pathogenesis of the most deadly of human malaria parasites, Plasmodium falciparum, is related to the capability of infected red blood cells to sequester in deep tissues. Sequestration is critical for the completion of the red blood cell cycle because the release of parasites into the blood circulation allows recognition by surveillance macrophages and clearance in the spleen. A series of studies have since led to the understanding that sequestration of asexually replicating parasites is caused by the adherence of parasite infected red blood cells to the vascular endothelium of various tissues in the body.
We have recently demonstrated that gametocytes, the only stage capable of transmission to the mosquito vector, develop in the extravascular environment of the human bone marrow. Preliminary studies in the mouse model have confirmed this finding and also suggest existence of an asexual reservoir in the bone marrow. In this innovative multidiscipinary proposal we aim to investigate the host pathogen interactions at the interface between infected red blood cell and bone marrow vasculature. Specifically we will focus on the following questions: how do parasites home to bone marrow? What are the changes in the bone marrow endothelium upon infection? How do parasites adhere with and transmigrate across the vascular endothelium in the bone marrow? The proposed studies initiate detailed characterization of a new paradigm in malaria parasite interaction with the host vasculature and provide a compelling new avenue for intervention strategies.
Max ERC Funding
2 298 557 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym C-POS
Project Children's Palliative care Outcome Scale
Researcher (PI) RICHARD HARDING-SWALE
Host Institution (HI) KING'S COLLEGE LONDON
Call Details Consolidator Grant (CoG), LS7, ERC-2017-COG
Summary Person-centred care is a core health value of modern health care. The overarching aim of C-POS (Children's Palliative care Outcome Scale) is to develop and validate a person-centred outcome measure for children, young people (CYP) and their families affected by life-limiting & life-threatening conditions (LLLTC). International systematic reviews, and clinical guides have highlighted that currently none exists. This novel study will draw together a unique multidisciplinary collaboration to pioneer new methods, enabling engagement in outcome measurement by a population currently neglected in research.
C-POS builds on an international program of work. The sequential mixed methods will collect substantive data through objectives to determine i) the primary concerns of CYP and their families affected by LLLTC & preferences to enable participation in ethical person-centred measurement (n=50); ii) view of clinicians and commissioners on optimal implementation methods (national Delphi study); iii) a systematic review of current data collection tools for CYP regardless of condition; iv) integration of objectives i-iii to develop a tool (C-POS) with face and content validity; v) cognitive interviews to determine interpretability (n=40); vi) longitudinal cohort of CYP and families to determine test-retest reliability, internal consistency, construct validity and responsiveness (n=151); vii) development of resources for routine implementation viii) translation and interpretation protocols for international adoption.
C-POS is an ambitious study that, for the first time, will enable measurement of person-centred outcomes of care. This will be a turning point in the scientific study of a hitherto neglected group.
Summary
Person-centred care is a core health value of modern health care. The overarching aim of C-POS (Children's Palliative care Outcome Scale) is to develop and validate a person-centred outcome measure for children, young people (CYP) and their families affected by life-limiting & life-threatening conditions (LLLTC). International systematic reviews, and clinical guides have highlighted that currently none exists. This novel study will draw together a unique multidisciplinary collaboration to pioneer new methods, enabling engagement in outcome measurement by a population currently neglected in research.
C-POS builds on an international program of work. The sequential mixed methods will collect substantive data through objectives to determine i) the primary concerns of CYP and their families affected by LLLTC & preferences to enable participation in ethical person-centred measurement (n=50); ii) view of clinicians and commissioners on optimal implementation methods (national Delphi study); iii) a systematic review of current data collection tools for CYP regardless of condition; iv) integration of objectives i-iii to develop a tool (C-POS) with face and content validity; v) cognitive interviews to determine interpretability (n=40); vi) longitudinal cohort of CYP and families to determine test-retest reliability, internal consistency, construct validity and responsiveness (n=151); vii) development of resources for routine implementation viii) translation and interpretation protocols for international adoption.
C-POS is an ambitious study that, for the first time, will enable measurement of person-centred outcomes of care. This will be a turning point in the scientific study of a hitherto neglected group.
Max ERC Funding
1 799 820 €
Duration
Start date: 2018-09-01, End date: 2023-02-28
